This invention relates to the treatment of type I diabetes.
Type 1 or Insulin Dependent Diabetes Mellitus (IDDM) is estimated to affect 675,000 people in the United States. This represents 0.3% of the total U.S. population, with an estimated 30,000 new cases diagnosed each year. Complications of diabetes impair the longevity and quality of life, and include atherosclerotic heart disease, gangrene and stroke, as well as diabetic retinopathy, neuropathy and nephropathy. Within 15 years after the onset of diabetes, retinopathy may be observed in 97% of Type 1 diabetics. Today diabetic retinopathy remains the leading cause of blindness in the U.S. and patients with diabetes are 25 times more likely to develop blindness than the general population.
Symptoms of diabetic neuropathy have been observed in 54% of Type 1 patients studied. Patients present with symptoms ranging from peripheral sensory-deficits (pins and needles/carpal tunnel syndrome) to autonomic neuropathy resulting in bladder and bowel dysfunction. Type 1 diabetes is also responsible for a large proportion of the patients on renal dialysis, the result of diabetes-induced end stage renal disease. More than 40% of Type 1 patients who have had diabetes for more than 20 years have diabetic nephropathy. The prevalence of myocardial infarction, angina and stroke is 2-3 times greater than in non-diabetics, and the Type 1 diabetic""s life span is shortened by about 15 years. The estimated total cost of Type 1 diabetes in the United States (medical expenses, lost wages etc.) is greater than $20 billion per year.
Type I diabetes actually begins before the clinical manifestations of the disease. It starts with the progressive destruction of beta cells in the pancreas. These cells normally produce insulin. The reduction of insulin response to glucose can be measured during this period, however. Ultimately there is massive ( greater than 90%) destruction of beta cells in the islets of Langer hans. During the early stages of the disease and beyond, type I diabetes is characterized by the infiltration of pancreatic islets by macrophages and lymphocytes (helper and killer). The macrophage infiltration is believed to prompt the infiltration of small lymphocytes. While clinicians understand the potential for a drug that can address macrophage involvement early in the disease, no safe therapies have yet been found. Current treatment involves daily frequent injections of insulin. However, this can lead to side effects such as hypoglycemic shock.
Thus, there is an urgent, unmet need for safe and effective drug therapies for type I diabetes, particularly a therapy that can intervene in the early stages of the disease to treat macrophage infiltration and prevent subsequent beta cell damage by macrophages.
This invention represents a novel therapy for treating patients (e.g., humans or companion animals) with type I diabetes without the substantial side effects of prior pharmaceutical approaches. Specifically, this invention involves the administration of an inhibitor of phosphodiesterase 2 (xe2x80x9cPDE2xe2x80x9d) to a mammal in need of treatment for type I diabetes. Preferably, that inhibitor also inhibits phosphodiesterase 5 (xe2x80x9cPDE5xe2x80x9d). In narrower aspects of this invention, this invention involves the administration of compounds of Formula I below to a mammal in need of treatment for type I diabetes.
As explained below, compounds that inhibit PDE2 can cause activated macrophages to undergo apoptosis.